Lack of effect after substitution of methylphenidate prolonged-release

Transcription

1 Lack of effect after substitution of methylphenidate prolonged-release Introduction Methylphenidate prolonged-release (Concerta, Equasym XL, Medikinet CR, Ritalin LA, Kinecteen ) is indicated for the treatment of attention deficit hyperactivity (ADHD) for children and adolescents between 6 and 18 years old [1]. The guideline of the Dutch Association for Psychiatry mentions methylphenidate as drug of first choice for treatment of adults with ADHD preferably with long-acting products [2]. Long-acting products, like Concerta, can be taken once daily minimizing the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily [1]. In the Netherlands, Concerta was granted market authorization on 21 November 2002 [1]. Since June 2014 two generics of Concerta have been authorized, namely methylphenidate prolongedrelease Sandoz as of October 2013 [3] and methylphenidate prolonged-release Mylan as of June 2014 [4]. In June 2016 Mylan was granted market authorization for an extra strength 27mg [5]. Both the Sandoz and Mylan products are considered to be bioequivalent to the reference product (Concerta) [4-6]. Reports From 8 April 2014 until 30 April 2017, the Netherlands Pharmacovigilance Centre Lareb received 75 reports of adverse drug reactions (ADRs) that occurred after substitution of methylphenidate prolonged-release. Reporters were both healthcare professionals and consumers with almost a fiftyfifty share. Of these reports, 29 concerned substitution of Concerta into methylphenidate prolongedrelease Sandoz, 36 Concerta into methylphenidate prolonged-release Mylan and two methylphenidate prolonged-release Sandoz into methylphenidate prolonged-release Mylan. There were also three reports concerning substitution of Concerta into methylphenidate prolonged-release of an unspecified brand, three reports where the previous used brand is unknown and two reports concerned substitution of Equasm XL or Medikinet CR, which are not bioequivalent to Concerta or its generics, into one of these. In the following sections the reports concerning substitution of Concerta into methylphenidate prolonged-release Sandoz or Mylan will be discussed in more detail. Table 1 Overview of the six types of substitution mentioned in the 75 reports concerning substitution of methylphenidate prolonged-release Substitution of Into Number of reports Concerta Methylphenidate prolonged-release Sandoz 29 Concerta Methylphenidate prolonged-release Mylan 36 Methylphenidate prolonged-release Sandoz Methylphenidate prolonged-release Mylan 2 Concerta Methylphenidate prolonged-release unknown brand 3 Methylphenidate prolonged-release unknown brand Equasm XL or Medikinet CR Methylphenidate prolonged-release unknown brand, Sandoz or Mylan Concerta or Methylphenidate prolonged-release Mylan 3 2 Substitution of Concerta into methylphenidate prolonged-release Sandoz Of the 29 reports concerning substitution of Concerta into methylphenidate prolonged-release Sandoz, 19 concerned males and ten females. The patients were between 8 51 years of age with a median of 18.5 years. Twenty-five reports mention changes in behavior and/or a decreased, shorter or no effect after substitution. These behavioral changes include abnormal behavior, aggression, anger, irritability, altered mood, concentration problems and daydreaming. None of the reports mentioning a shorter or decreased effect specify the shorter effect in time. Four reports mention only general ADRs, like nausea, headache and somnolence. In about half of the reports the reports the reactions started within one day after substitution with eight reports mentioning a time to onset of one hour or less. In 83% of the reports reactions started within one week after substitution. Eighteen reports mention recovery after switching back to Concerta and in three reports the patients recovered after withdrawal of methylphenidate prolonged-release Sandoz. Time to recovery is mostly unknown, but if mentioned

2 this was shortly after withdrawal or re-substitution. All 29 reports can be found in Table 1 in the appendix. Reports concerning substitution of Concerta into methylphenidate prolonged-release Mylan Of the 36 reports concerning substitution of Concerta into methylphenidate prolonged-release Mylan, 19 concerned females and 17 males. The patients were between 8 57 years of age with a median of 14 years. Thirty-five reports mention behavioral changes, a suspected irregular or unreliable release and/or a decreased, shorter or no effect after substitution. One report mentions none of these reactions. The behavioral changes include sleeping s, abnormal behavior, agitation, aggression, restlessness, concentration problems, mood swings and depressed mood. Five reports co-report a product quality issue, namely the falling apart of tablets when stored in the original container. Only one of the reporters mentions that this is the cause of the previously mentioned unreliable release of methylphenidate from the tablets. In eight reports the shorter effect is specified; the effect of Concerta is in a range of 7 12 hours and the effect of methylphenidate prolongedrelease Mylan between 4 8 hours. In about half of the reports the reactions started within one day after substitution with seven reports mentioning a time to onset of one hour or less. In 83% of the reports reactions started within one week after substitution. Twenty-three reports mention recovery after switching back to Concerta and in four reports the patients recovered after withdrawal of methylphenidate prolonged-release Mylan. Time to recovery is mostly unknown, but if mentioned this was shortly after withdrawal and/or switching back to Concerta. All 36 reports can be found in Table 2 in the appendix. Literature Adverse reactions The Summary of Product Characteristics (SmPC) of methylphenidate prolonged-release products describe various behavioral and psychic reactions as side effects, for example: aggression, agitation, depression, insomnia, restlessness and mood changes. These reactions are mentioned as common (up to 1 in 10 people) or uncommon (up to 1 in 100 people) [1,3-5]. Release systems and effectiveness Both Concerta and methylphenidate prolonged-release Sandoz have an osmotic controlled release system [7,8]. The methylphenidate in the outer layer provides the immediate release while the methylphenidate within the membrane is delivered at a first-order rate for a longer period after administration [9]. Methylphenidate prolonged-release Mylan contains an immediate release fraction and a prolonged-release fraction the latter provided by sugar spheres [4,5]. For Concerta and methylphenidate prolonged-release Sandoz it is advised not to divide the tablets, but the three highest strengths of methylphenidate prolonged-release Mylan are pre-scored, so they can be easily halved [1,3-5]. Both oral intake of Concerta and methylphenidate prolonged-release Sandoz, results in an initial maximal concentration of methylphenidate after 1-2 hours. The maximum plasma concentration is reached after 6-8 hours after which the concentration methylphenidate slowly decreases [1,3]. For methylphenidate prolonged-release Mylan the immediate-release phase results in a maximum plasma concentration after 1.35 hours and the prolonged-release phase gives a second peak after 5.3 hours [4,5]. The effect of all three products should last for 12 hours after a once daily intake in the morning [1,3-5]. In May 2015, the Danish Pharmacovigilance Centre reported that they had tested methylphenidate prolonged-release Sandoz as a response to many reports of substitution problems and lack of efficacy after switching from Concerta to Sandoz. The results showed similarity between Concerta and methylphenidate prolonged-release Sandoz and the Danish Pharmacovigilance Centre concluded that based on the laboratory results there is no difference between both products. But they considered the number of ADR reports to be a signal which was forwarded to the drug regulatory agency responsible for monitoring all methylphenidate-containing products in the EU [10].

3 Methylphenidate cost, reimbursement and prescription data In the Netherlands most drugs are reimbursed out of the basic healthcare insurance. For some drugs patients have to pay an own contribution which could be paid for by their insurance if they have an additional insurance package. One of these drugs is methylphenidate prolonged-release [11]. Most Dutch healthcare insurance companies have a preference policy regarding drug brands they reimburse, for example one of the healthcare insurance companies has chosen methylphenidate prolonged-release Mylan as their preference product in 2017 for methylphenidate prolonged-release products [12]. Table 2 Price of Concerta, methylphenidate prolonged-release Sandoz and methylphenidate prolonged-release Mylan per 30 tablets as of June 2017 [13] Strenght Concerta Methylphenidate prolongedrelease Sandoz Methylphenidate prolongedrelease Mylan Costs Own contribution Costs Own contribution Costs Own contribution 18 mg mg mg mg Table 3 Number of patients using methylphenidate prolonged-release in the Netherlands from [14] Concerta 18 mg 17,098 17,121 16,600 16,131 11,072 Concerta 27 mg 14,557 16,072 16,905 17,635 18,536 Concerta 36 mg 30,397 31,222 31,761 28,513 20,859 Concerta 54 mg 20,696 22,086 23,233 21,456 15,948 methylphenidate prolonged-release 18 mg brand unknown ,881 8,085 methylphenidate prolonged-release 27 mg brand unknown methylphenidate prolonged-release 36 mg brand unknown ,511 17,811 methylphenidate prolonged-release 54 mg brand unknown ,005 13,427 Discussion and conclusion In the Netherlands, drug substitution is often the result of the preference policy of healthcare insurance companies or of drug shortages. For methylphenidate prolonged-release products there can be three reasons of substitution, namely: i) the preference policy of healthcare insurance companies, ii) to reduce the own contribution of the patient or iii) pharmacies dispense the for them financially most preferable drug brand depending on the contract they have with the healthcare insurance companies [15]. substitution of brands into generics often leads to complaints as patients have a poor opinion of and mistrust in generics [16]. A review by Håkonsen et al showed that 8-34% of patients having their drugs substituted into a generic reported poorer effects and/or new side effects after substitution [17]. The reports of ADRs after substitution received by Lareb concern mostly changes in behavior and/or a decreased, shorter or no effect after substitution. Behavioral changes are symptoms of ADHD, but in the reports stands out that most patients, often children, recovered after switching back to Concerta. So the reported behavioral changes, like daydreaming and concentration problems, are likely to be signs of a decreased effect after substitution. The times to onset of the various reactions vary from minutes to a few months after substitution. The short times to onset could be the result of a difference in release of the immediate-release phase, while longer times to onset could be explained that parents and caretakers realized only at a later stage that the child s behavior had changed for a longer period. Although there are seven reports that mention a shorter or decreased effect after switching from Concerta to methylphenidate prolonged-release Sandoz, none of these specify this shorter effect in

4 time. But half of the reports of a shorter or decreased effect after substitution of Concerta to methylphenidate prolonged-release Mylan mentioned that Mylan works 3 4 hours less than Concerta. During the repeat-use mutual recognition procedure, Germany and the Netherlands expressed their concerns about bioequivalence in a fed-study for the immediate-release phase between Concerta and Sandoz. They highlighted that the use of partial metrics under fed condition was considered necessary as Concerta, the reference product, can also be taken with food. Therefore bioequivalence under fed conditions for the two phases of absorption (immediate and prolonged-release phase) should be demonstrated. Sandoz augmented that this was the result of intra-individual differences [6]. The subject of the referral was the design of the fed study, in which a high variability was observed and the confidence intervals for the ratios of Cmax0-2 and AUC0-2 (partial metrics for the first absorption phase) were outside the standard limits of %. However, according to the MEB, it is known from the innovator dossier that the first absorption phase is characterized by a very high intrasubject variability under fed conditions due to subject-related physiological effects. During the referral procedure, it was concluded however, that since the point estimates for both Cmax and AUC in the first absorption phase were close to 100%, there is no indication towards different plasma concentrations for the generic formulation, and the observed variability was due to subject-related physiological effects and not due to inferior quality of the generic formulation. Therefore, widening of the limits for confidence intervals was agreed upon and bioequivalence under fed conditions between Methylphenidate Sandoz and Concerta has therefore been concluded. For the reported ADRs after substitution from Concerta into methylphenidate prolonged-release Mylan, the difference in release system (osmotic controlled release vs delayed release via sugar spheres) could be the explanation for the difference in effect. This is supported by the difference in pharmacokinetic parameters as the initial peak concentration is seen after 2 hours with Concerta vs 1.35 hours with Mylan and the second peak concentration after 6-8 hours vs 5.3 hours respectively. As Sandoz also has an osmotic controlled release system, two cases Lareb received of substitution problems after switching from Sandoz to Mylan could be seen as supportive (Table 3 in appendix). One of these cases mentions that when the patient switched from Concerta to Sandoz he experienced no ADRs, but after substitution of Sandoz into Mylan the patient experienced three hour less effect with Mylan compared to Sandoz. However, according to the MEB, the different pharmacokinetic parameters reported in the SPC of Methylphenidate Mylan as compared to Concerta does not imply that Methylphenidate Mylan has a different pharmacokinetic profile or that Methylphenidate Mylan is not bioequivalent to Concerta. This is reflected in section 5.2 the Mylan SmPC [4,5]. This signal focused on reports of ADRs and lack of efficacy following substitution of Concerta into one of its generics. Taking into account the previous investigation into reports of substitution problems of after switching from Concerta to Sandoz and the specifics of the reports of substitution of Concerta to Mylan, the current focus should be on the reports where the difference in release system could be explanatory for the reported ADRs and lack of efficacy. References 1. Dutch SmPC methylphenidate prolonged-release (Concerta ). (version date: , access date: ) 2. [NVvP Richtlijn ADHD bij volwassenen]. (version date: , access date: ) 3. Dutch SmPC methylphenidate prolonged-release Sandoz. (version date: , access date: ) 4. Dutch SmPC methylphenidate prolonged-release Mylan 18mg, 36mg, 54mg. (version date: , access date: ) 5. Dutch SmPC methylphenidate prolonged-release Mylan 27mg. (version date: , access date: ) 6. CHMP Methylphenidate Sandoz Article-29 referral - Assessment report. (version date: , access date: ) 5.pdf. 7. [Farmacotherapeutisch Kompas] - Methylphenidate. (version date: , access date: ) 8. Schapperer E, Daumann H, Lamouche S, Thyroff-Friesinger U, Viel F, Weitschies W. Bioequivalence of Sandoz methylphenidate osmotic-controlled release tablet with Concerta(R) (Janssen-Cilag). Pharmacol Res Perspect. 2015;3(1):e00072

5 9. Swanson J, Gupta S, Lam A, Lerner M, Modi N, Lindemulder E, Wigal S. Development of a new once-a-day formulation of methylphenidate for the treatment of attention- : proof-of-concept and proof-of-product studies. Arch Gen Psychiatry 2003;60(2): DHMA Danish Pharmacovigilance Update - ADR reports of substitution problems and lack of efficacy of Methylphenidate "Sandoz". (version date: 2015, access date: ) Rijksoverheid - Vraag en Antwoord: Welke medicijnen krijg ik vergoed? (version date: 2017, access date: ) VGZ - Reglement Farmaceutische Zorg (version date: 2017, access date: ) Netherlands Health Care Institute - Medicine Prices [Medicijnkosten.nl]: Methylphenidate. (version date: , access date: ) GIPdatabase - Information System of the Dutch Health Care Insurance Board. (version date: , access date: ) Personal Communication BENU. Nov Dunne SS, Dunne CP. What do people really think of generic medicines? A systematic review and critical appraisal of literature on stakeholder perceptions of generic drugs. BMC.Med. 2015;13: Håkonsen H, Toverud EL. A review of patient perspectives on generics substitution: what are the challenges for optimal drug use. Generics and Biosimilars Initiative Journal 2012;1(1): Appendix 1 Table 1. Reports of ADRs after drug substitution of Concerta into methylphenidate prolonged-release Sandoz Patient, Sex, Age Suspected ADRs (other than Action with drug, A mva 36mg, Attention, nausea, abdominal pain 2 hours, recovered B mva 54mg, Attention aggressive behaviour. 48 hours, C F, 8-10 Hospital pharmacist mva 54mg, Attention Atomoxetine, aripiprazol, methylphenidate, abnormal behaviour, aggressive behaviour, 0 days, D mva 54mg, ADHD Melatonine decreased, gastrointestinal discomfort 2 days, E F, General Practitioner mva 54mg, Attention, tablet in stool 4 days, F F, mva 54mg, ADHD decreased G mva 54mg, Concentration impairment (controlled release differs from Concerta ) Unknown weeks, not yet recovered H mva 36mg, Attention 2 days, Dose not changed, not recovered

6 Patient, Sex, Age Suspected ADRs (other than Action with drug, I, , mva 54mg, ADHD J, , mva 36mg, ADHD drug effect decreased Unknown K, , L, , M, , N, , F, O, , M, P, , M, Q, , F, R, , S, , F, T, , U, , mva 36mg, ADHD mva 18 mg, Autism mva 36 mg, ADHD mva 36 mg, Attention deficit mva 54mg, Attention mva 54 mg, Attention mva 18 mg, Pervasive developmental oxcarbazepine, levetiracetam estradiol/norethist eron, fluoxetine drug effect decreased nausea, malaise mood altered, dizziness decreased < 1 month, 4 days, 7 days, Dose not changed, trazodon somnolence 2 weeks, Dose not changed, Melatonine nitrazepam depressed mood, sleep, suicidal ideation abdominal discomfort,, Within a day, 2 days, 30 minutes, 30 minutes, 30 minutes,

7 Patient, Sex, Age V, , W, , X, , Y, , F, Z, , AA, , AB, , AC, , F, mva 54mg, Attention mva 54mg, use for unknown indication deficit mva 54 mg, Attention mva 18mg, Attention deficit sertraline colecalciferol Suspected ADRs (other than nausea nausea, throat irritation, headache decreased decreased, headache, thirst, dry mouth daydreaming, irritability, drug ineffective headache, chest discomfort, agitation, anger, disturbance in attention, fatigue, paraesthesia oral, swollen tongue, dizziness Action with drug, 15 minutes, Dose not changed, Unknown hours, Unknown 2 weeks, Unknown days, Recovering minutes - 3 hours, Patient B, C, D, E, F, I, K, L, M, N, Q, R, S, T, U, X, Z, AA: after withdrawal Sandoz and switching back to Concerta Patient A, AB, AC: after withdrawal of Sandoz, unknown if Concerta was restarted Patient G, J: Unknown if patient recovered after withdrawal Sandoz and switching back to Concerta Patient H, O, P: No withdrawal of Sandoz. Patient V, W, Y: Unknown if Sandoz was withdrawn

8 Table 2. Reports of ADRs after drug substitution of Concerta into methylphenidate prolonged-release Mylan Patient, Sex, Age A, , F, B, , M, C, , D, , M, E, , F, , M, General Practitioner G, , F, H, , I, , J, , F, mg, ADHD 18 mg, 54 mg, Attention deficithyperactivity 36 mg, ADHD 36 mg, ADHD 54 mg, Attention 36mg, Attention 36mg, Attention 18mg, Attention ethinylestradiol/ levonorgestrel Suspected ADRs (other than headache, panic attack, fatigue, mood swings, dizziness, psychomotor hyperactivity, dry throat, muscle tightness, vision blurred Action with drug minutes 3 hours, unknown, not recovered 6 hours, unknown, insuline aspart Within 1 week, desloratadine cetirizine, colecalciferol feeling hot, dyspnoea, cough, headache, tremor decreased, nausea, gastrooesophageal reflux disease, restlessness, agitation depressed mood, decreased appetite, insomnia restlessness, visual impairment aggression, emotional, suicidal ideation decreased decreased Within a few days, Positive rechallenge 2 hours, Recovering 20 days, Recovering 6 hours,

9 Patient, Sex, Age Suspected ADRs (other than Action with drug K, , 18mg, Attention deficit ethinylestradiol/ drospirenon, desloratadine, fluticasone, paracetamol anxiety, lethargy, aggression, mood swings, myalgia, arthralgia pain in extremity, feeling abnormal 7 days, 14 days, L, , 54mg, Attention deficit Cetirizine decreased 5 hours, M, , F, 41-50, 54mg, Attention Short-acting methylphenidate decreased, product quality issue 2 days, N, , F, mg, 54mg, Attention deficithyperactivity 2 hours, O, , 18mg, 54mg, Attention deficithyperactivity decreased 5 days, P, , M, mg, Attention deficit citalopram decreased, product quality issue Within days, Q, , M, mg, Attention tremor, sleep, nausea Within days, Unknown R, , M, mg, Attention fluticasone dry mouth, agitation, sleep, hyperhidrosis, abnormal dreams S*, , F, mg, 54mg, Attention deficit methylphenidate mga (Medikinet CR), ethinylestradiol/ levonorgestrel unexpected (controlled release unreliable), product quality issue 3 hours, T, , 36mg, Attention decreased, product quality issue Within 2 months,

10 Patient, Sex, Age U, , F, V, , W, , X, , Y, , F, Z, , F, AA, , F, AB, , M, AC, , M, AD, , 36mg, 18mg, Attention deficit 36mg, Attention 54mg, Attention deficit deficit 54mg, 36mg, ADHD 54mg, Attention 36 mg, 54 mg, Attention deficithyperactivity 27 mg, Attention Suspected ADRs (other than, rebound effect, initial insomnia, product quality issue peripheral coldness, depressed mood, drug effect decreased irritability, disturbance in attention, abnormal behaviour depressed mood, panic attack Action with drug 8 hours, 1-7 hours, methylphenidate nausea, affect lability 10 minutes, venlafaxine Aggression, depressed mood, mood swings product quality issue (irregular release) agitation, head discomfort, fatigue, disturbance in attention shortened, executive dysfunction Dose not changed, Unknown 4 days, 1 week,

11 Patient, Sex, Age AE, = , AF, , AG, , AH, , AI, , AJ, , methylphenidate Mylan tablet 10mg, 36 mg, Attention 27 mg, Attention 36 mg, Autism 54 mg, Attention 27 mg, Attention Short-acting methylphenidate Short-acting methylphenidate Suspected ADRs (other than rebound effect, irritability, restlessness, therapeutic response shortened, disturbance in attention shortened, fatigue, educational problem shortened, tic, disturbance in attention, condition aggravated shortened, disturbance in attention, malaise, executive dysfunction, irritability shortened, rebound effect, educational problem irritability, disturbance in attention, nausea, abdominal pain, abnormal behaviour Action with drug METHYLPHENIDATE TABLET 10MG 2 weeks,, METHYLPHENIDATE TABLET MGA 36MG 2-3 weeks, 1 week, 1 week, 2 weeks, 1 week, Several days, * Reporter mentions the split tablets result in a decreased effect Patient C, D, E, F, H, I, J, L, M, N, P, R, S, U, V, AA, AD, AF, AG, AH, AI, AJ: after withdrawal of Mylan and switching back to Concerta Patient AE: after withdrawal of Mylan and switching back to Concerta. Also these reaction with short-acting methylphenidate Mylan of which patient recovered after switching to short-acting methylphenidate Sandoz Patient K, O, Q, X : Unknown if patient recovered after withdrawal Sandoz and switching back to Concerta Patient G, T, W, Y: Unknown if patient switched back to Concerta after withdrawal Mylan Patient A, B, Z, AB, AC: Unknown if Mylan was withdrawn Patient B: Effect of Mylan is 2-3 hours shorter then Concerta Patient I: Effect Concerta hours, Mylan 7-8 hours Patient J: Effect Concerta 11 hours, Mylan 6,5 hours Patient L: Effect Concerta 10 hours, Mylan 5 hours Patient M: Effect Concerta 7-8 hours, Mylan 4 hours. Patient AD, AE, AF: Effect Concerta 12 hours, Mylan 8 hours Patient AG: Effect Concerta 11 hours, Mylan unknown

12 Table 3. Reports of ADRs after drug substitution of methylphenidate rolonged-release Sandoz into methylphenidate prolonged-release Mylan Patient, Sex, Age A, , M, B, , M, mg, ADHD olanzapine, folic acid Suspected ADRs (other than decreased Action with drug 6 hours, Patient A: after withdrawal of Mylan and switching back to Sandoz. Had no complaints when switching from Concerta to Sandoz Patient B: after withdrawal of Mylan and switching back to Sandoz Patient A: Effect Concerta, Sandoz 8-9 hours, Mylan 5-6 hours This signal has been raised on October 30, It is possible that in the meantime other information became available. For the latest information, including the official SmPC s, please refer to website of the MEB